The invention relates generally to bicyclic carbohydrates that are useful in the treatment of infections caused by parasites and, more specifically, to such compounds useful in the treatment or amelioration of infections caused by protozoa.
Protozoa are single-celled animals. Many species are important parasites of humans, the infections being most prevalent in tropical and subtropical regions, but also occurring in temperate regions. Transmission of protozoan parasites can occur in many ways, the two most common being injection by the bites of blood-sucking insects and accidental ingestion of infective stages. The geographic restriction of some species reflects both the distribution of vector insect species and the climatic conditions necessary for the parasites to complete their development in the insect. Orally acquired infections are favored by low standards of social and personal hygiene, and by increased survival of infective stages in warm damp conditions.
Protozoa infect body tissue and organs as intracellular parasites in a wide variety of cells or as extracellular parasites in the blood, intestine or urinogenital system.
One example of protozoa that cause diseases in humans are trypanosomes. Trypanosomes have been around for more than 300 million years. They are microscopic unicellular protozoa that are ubiquitous parasites of insects, plants, birds, bats, fish, amphibians and mammals. Because they have been around for so long, they and their natural hosts have evolved together to ensure their mutual survival. Trypanosomes can be found worldwide. Fortunately, few species of trypanosomes are pathogenic. Trypanosomes, and other parasites, mainly cause disease when they spread to new hosts, like humans and their domestic animals, especially recent imports into endemic areas of species that diverged since continents separated.
Generally trypanosomes are associated with diseases in Africa and South America. The related Leishmania organisms have a wider distribution. African trypanosomiasis is infection prevalent throughout Latin America, extending to the southern borders of the United States.
Transmission of human-infective trypanosomes occurs primarily through insects that feed upon us. The insect vectors, however, are very specific. The reason is that transmission usually requires the parasite to multiply and undergo specific developmental transitions in the insect. In fact, trypanosomes may originally have been purely parasites of insects. Adaptation to mammalian hosts was probably a late event in their evolution.
The African sleeping sickness, caused by trypanosomes, is transmitted to humans through the bite of the tsetse fly of the genus Glossina. There are two forms, each caused by a different parasite: Trypanosoma brucei gambiense, which causes a chronic infection lasting years and affecting countries of western and central Africa; and Trypanosoma brucei rhodeseinse, which causes acute illness lasting several weeks in countries of eastern and southern Africa.
Once inoculated into the human host by an infected tsetse fly, T. brucei proliferates and invades all organs. The host mounts an adaptive immune response which kills most of the invading parasites. But the trypanosome has the capacity to vary the composition of its surface coat protein antigens and thus a small number evade the immune system and multiply exponentially. The trypanosome can express thousands of variant proteins. The immune system eventually becomes exhausted by these repeated challenges, and the parasite develops in lymph and blood, causing a variety of debilitating conditions. The parasite can also invade the nervous system, leading to the characteristic “sleeping sickness” in which patients fall into a coma and die. The neurological alterations caused by trypanosomes are often irreversible even after successful treatment. Without treatment, the disease is invariably fatal.
The sleeping sickness is a daily threat to more than 60 million men, women and children in 36 countries of sub-Saharan Africa, 22 of which are among the least developed countries in the world. The estimated number of people thought to have the disease is between 300,000 and 500,000.
Most infected people only seek treatment when the disease has already advanced to the second stage. The most common treatment at this stage is melarsoprol (Arsobal, Specia), an archaic drug introduced in 1949. Melarsoprol contains arsenic, is extremely painful when injected, and kills outright 3–10% of patients treated. Furthermore, it is becoming less and less effective because the parasite has developed resistance to the drug. In some areas of Africa, such as Omugo, Uganda or Ibba, South Sudan where sleeping sickness programs are being ran, the drug fails to cure 25–30% of patients.
There is a safer, more effective alternative to melarsoprol called eflornithine (or DFMO). Its spectacular success at pulling people out of a coma led to its nickname, the “resurrection drug”. However, Aventis ceased production in 1995, only five years after it first reached the market. Exclusively used to treat a disease of the poor, eflornithine was not profitable. Momentarily, WHO and Aventis have set up a program to combat the disease based on a three-point strategy: specific drug donation, disease management and research & development.
Although eflornithine is the only registered drug that can cure the melarsoprol-refractory form of the disease, nifurtimox (Lampit, Bayer) has also been used with good results.
Suramin (Germanin, Bayer) is considered the drug of choice for the therapy of early Trypanosoma rhodesiense sleeping sickness. However, it is a toxic drug that requires close medical supervision (WHO Expert Committee on Onchocerciasis. Technical Report Series #335. Geneva Switzerland: World Health Organization, 1966); its more severe side effects include immediate collapse and renal damage (Fain A. Toxic reactions after a single injection of bayer 205 given for prevention of trypanosomiasis. Rev Sc Med Cong Belge 1942:137; Chestenman C. The therapeutic effect of bayer 205 in trypanosomiasis of the central nervous system. Trans Soc Trop Med Hyg 1924;18:311). Also Bayer has agreed to provide a product (Germanin) to the WHO free of charge for an initial 5-year period. Suramin is no longer used as a prophylactic agent in African trypanosomiasis or as a therapeutic agent in early Gambian sleeping sickness because pentamidine (Lomodine, Pentam) is more effective in these situations (WHO Expert Committee on Trypanosomiasis, First Report, Technical Report Series #247. Geneva, Switzerland: World Health Organization, 1962).
According to the Website of Médecins Sans Frontières, it is unlikely that a new drug for sleeping sickness will be available in the near future (http://www.accessmed-msf.org/campaign/slp01.shtm). Except for eflornithine, whose effectiveness against sleeping sickness was discovered by chance, there has been no significant improvement in treatment for 50 years. In spite of the millions of people at risk, research into the human form of sleeping sickness is negligible. As is the case for other diseases such as river blindness and leishmaniasis, the veterinary industry may be the only hope, since the private sector is researching a form of the disease that infects cattle. This work may prove useful, as some of the drugs developed for the animal form of the disease may be effective in humans. But no drugs have been approved for human use and it will take a long time to study their effectiveness and obtain authorization for use. Some public funding has been allocated for research into a shorter treatment course for melarsoprol, but this toxic drug is still far from adequate.
Visceral leishmaniasis is caused by the protozoa L. donovani, named for William Leishman who first described it in London in 1903. The illness is distributed all over the world but predominantly is encountered in India, South America, Central Asia, Middle East and Africa. The spectrum of illness ranges from asymptomatic infection to severe life-threatening infection also known as kala azar, Dumdum fever, Black fever, Assam fever and infantile splenomegaly in various parts of the world.
The Leishmania species infecting humans are mainly Leishmania donovani causing visceral leishmaniasis and Leishmania tropica and Leishmania brasiliensis causing cutaneous leishmaniasis. Leishmania are obligatory intracellular parasites and are transmitted by the bite of a tiny 2- to 3-millimeter insect vector, the sandfly belonging to the genera Phlebotomus and Lutzomyia. The number of cases of leishmaniasis is increasing, mainly because of man-made environmental changes that increase human exposure to the sandfly vector. Another risk factor is the movement of susceptible populations into endemic areas, including large-scale migration of populations for economic reasons.
The parasite exists in 2 forms, the amastigote form and the promastigote form. The amastigote form occurs in humans, whereas the promastigote form occurs in the sandfly and in artificial culture. Only the female sandfly transmits the protozoa, infecting itself with the Leishmania parasites contained in the blood it sucks from its human or mammalian host. Resulting symptoms range from self-healing localized ulcers to widely disseminated progressive lesions of the skin, mucus membranes and the entire reticuloendothelial system. Parasitized macrophages disseminate infection to all parts of the body but more so to the spleen, liver and bone marrow. The spleen is enlarged with a thickening of the capsule, it is soft and fragile, its vascular spaces are dilated and engorged with blood, and the reticular cells of Billroth are increased markedly and packed with the amastigote forms of the parasite. However, no evidence of fibrosis is present. In the liver, the Kupffer cells are increased in size and number and infected with amastigote forms of Leishmania. Bone marrow turns hyperplastic, and parasitized macrophages replace the normal hemopoietic tissue. Leishmania sis infections are considered to be zoonotic diseases because the infection is being maintained in endemic areas in dogs, wild rodents and other animals.
Coexistence of leishmaniasis with HIV adds a serious dimension to the problem. Leishmaniasis is spreading in several areas of the world as a result of the rapidly spreading epidemic of AIDS. Co-infection with HIV has lead to the spread of leishmaniasis, typically a rural disease, into urban areas. In patients infected with HIV, leishmaniasis accelerates the onset of AIDS by cumulative immunosuppression and by stimulating the replication of the virus. It also may change asymptomatic Leishmania infections into symptomatic ones.
To overcome emerging resistance of protozoa against currently used medicines, new products are urgently needed.